Thiazetidine derivatives

ABSTRACT

Compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof, R 1  is hydrogen, alkyl or phenyl unsubstituted or substituted by one or two halo moieties, R 2  is hydrogen or alkyl, A CX wherein X is halo, B is O or NR 3  wherein R 3  is hydrogen, alkyl, acyl, haloacyl, 2alkoxycarbonyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl are useful for treating bacterial infections in humans and animals.

The present invention is concerned with thiazetidine derivatives whichare useful for their antibacterial activity.

It is known to treat gram-negative bacterial infections with such agentsas nalidixic acid, pyromidic acid, pipemidic acid, enoxacin (AT-2266),ofloxacin (DL-8280) inter alia. However, none of these providessatisfactory treatment for chronic infections caused by Pseudomonasaeruginosa or gram-positive bacterial infections caused by more virulentgram-positive bacteria.

The present invention is based on the discovery that thiazetidinederivatives are particularly useful for treating gram-negative bacterialinfections such as Pseudomonas aeruginosa and gram-positive bacterialinfections. More particularly, the present invention is concerned withthiazetidine derivatives of the formula ##STR2## and pharmaceuticallyacceptable salts thereof wherein R¹ is hydrogen, alkyl, preferably loweralkyl, or aryl, preferably phenyl unsubstituted or substituted by one ortwo halo moieties, R² is hydrogen or alkyl, preferably lower alkyl, A isN or CX wherein X is halo, B is O or NR³ wherein R³ is hydrogen, alkyl,preferably lower alkyl, acyl, haloacyl, alkoxycarbonyl, preferably loweralkoxycarbonyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl. Thecompounds have been found to be particularly useful for theirantibacterial activity and are thus useful for the treatment ofbacterial infections both caused by gram-negative and by gram-positivebacteria. Because of their low toxicity, they are useful for treatingsuch infections in humans and animals.

According to one embodiment of the present invention, the alkyl group ofR¹, R² and R³ is straight or branch chain alkyl preferably of 1 to 6carbon atoms for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl andisohexyl.

According to another embodiment of the present invention, the arylmoiety of R¹ is preferably phenyl which is either unsubstituted orsubstituted by 1 or 2 halo substituents, particularly by fluoro,especially difluoro. Particularly preferred R¹ are phenyl,4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl and3,5-difluorophenyl.

According to a further embodiment of the present invention, the acylmoiety of R³ is a straight or branch chain moiety having from 1 to 6carbon atoms such as for example, formyl, acetyl, propionyl, n-butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl and n-hexanoyl or haloacylsuch as mono-, di- or tri-halo substituted acyl especiallytrifluoroacetyl.

The alkoxycarbonyl group of R³ is a straight or branch chain moietypreferably of 2 to 5 carbon atoms for example, methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andn-butoxycarbonyl.

The halo moieties of X are chloro, bromo, fluoro and iodo preferablychloro or fluoro.

When the compounds of the present invention are in the form ofpharmaceutically acceptable salts, they are preferably salts of mineralacids such as the hydrochloride, sulfate, nitrate, phosphate,hydrofluoride, hydrochloride or salts of organic acids such as formate,acetate, tartate, lactate, citrate, fumarate, maleate, succinate,methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate,naphthalenesulfonate or camphorsulfonate. Pharmaceutically acceptablesalts according to the present invention also include salts of alkalimetals or alkaline earth metals such as sodium, potassium, calcium andthe like. The compounds of the present invention are produced inaccordance with the following methods. ##STR3##

In the above reaction, R¹, A and B are as above defined with respect toformula (I). Y and Z are the same or different and each is halo. R⁴ isalkyl, especially lower alkyl. ##STR4##

In the above reaction, R¹, R⁴, A, B, Y and Z are as above defined withrespect to Method-A. ##STR5##

In the above reaction, R¹, R⁴, A and B are as above defined with respectto Method-A. M is halo or alkylsulfinyl, especially lower alkylsulfinyl.##STR6##

In the above reaction, R¹, A and B are as above defined with respect toMethod-A. M is halo or alkylsulfinyl, especially lower alkylsulfinyl.

As can be seen from above Methods-A through D, the compounds of thepresent invention can be produced by two typical reaction routes.According to one route, a thiazetidine ring is formed from a startingmaterial of a naphthyridine-carboxylic acid orpyridopyrimidine-carboxylic acid substituted by a morpholine moiety or asubstituted or unsubstituted piperazine moiety (hereinafter referred toas an "amine": Method A and Method B). According to the other process athiazetidine ring is formed followed by the introduction of an amineinto the ring-containing compound (Method C and Method D). These fourprocesses will be discussed in more detail below.

Method-A

Compound II is reacted with a dihalide (for example, methylene iodide,ethylidene bromide, benzylidene bromide) in a solvent which is inert tothe reaction, in the presence of a base for example, sodium carbonate,potassium carbonate, triethylamine or the like, generally at atemperature of from about 0° C. to about 120° C. for the purpose ofpreparing the cyclized compound Ia.

Suitable solvents are aprotic solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide or sulforan. The amount ofdihalide and base to be used is preferably from 1.1 to 2.5 mols per molof compound II. In order to accelerate the reaction, sodium iodide orpotassium iodide (0.01 to 3.0 molar equivalents) may be added to thereaction.

Method-B

Compound II and a halide (ZCH₂ --R¹) are reacted, using the samereaction solvent and base as those described in the Method-A, generallyat a temperature of from about 0° C. to 80° C. to prepare compound IV.Thereafter, the resulting compound IV is halogenated with a suitablehalogenating agent (for example, N-bromo-succinimide,N-chlorosuccinimide or the like) in an inert solvent (for example,halogenated hydrocarbon solvents such as chloroform, dichloromethane orcarbon tetrachloride), to prepare compound V. Compound V is cyclized,using the same reaction solvent and base as those described in theMethod-A, generally at a temperature of from about 0° C. to about 80° C.to prepare compound Ia.

Method-C

Compound VI is condensed with an amine to prepare compound Ia. Inaccordance with this process, compound VI is reacted with an amine in asuitable solvent which is inert to the reaction (for example, aproticsolvents such as N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, sulforan, acetonitrile), and optionally in thepresence of a base (such as sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate or triethylamine)generally at a temperature of from about 0° C. to about 80° C., forexample at 40° C. to 60° C. The amount of the amine to be used is from1.5 to 2.5 mols per mol of compound VI.

Method-D

Compound VI is hydrolyzed with an acid (for example, concentratedsulfuric acid, fuming sulfuric acid, polyphosphoric acid or a mixturethereof) to prepare compound VII. The reaction is carried out in thepresence of an excess amount (one to 30 times by weight, preferably 5 to10 times by weight) of an acid as a solvent, generally at a temperatureof from about 0° C. to about 60° C. The hydrolyzing reaction may also becarried out in 20 to 30 times by weight (preferably 5 to 10 times byweight) of a 1% to 5% potassium hydroxide or sodium hydroxide-containingaqueous alcohol (e.g., methanol, ethanol, propanol, butanol, preferablytert.butanol), generally at about room temperature to about 60° C.

Next, compound VII is reacted with an amine in the same solvent as thatused in the Method-C to prepare compound Ib. The reaction is carried outgenerally at a temperature of from about 0° C. to about 60° C.,preferably at 0° C. to room temperature.

According to a further method of the present invention, the compounds ofthe formula I can also be obtained from a compound of the formula VIIIin accordance with reaction scheme set forth below: ##STR7##

In the above reaction, R¹, R², A and B, are as defined with respect toformula I.

More particularly, compound VIII is reacted with a dihalide in thepresence of a base (for example, potassium carbonate) in an inertsolvent (for example, N,N-dimethylformamide). That reaction may becarried out in a manner analogous to that described above with respectto Method-A. Thereafter, compound IX is subjected to a ring closingreaction which is carried out by techniques per se known to producecompounds of the formula I. For example, acidic substances such asphosphorus oxychloride, phosphorus pentachloride, phosphorustrichloride, thionyl chloride, fuming sulfuric acid, concentratedsulfuric acid, polyphosphoric acid, polyphosphoric acid esters or thelike may be used.

When an acidic substance is used, the amount of the acidic substance tobe used for the process is from one mol to a large excess amount,preferably from 20 to 30 mols per mol of compound IX. The reaction isgenerally carried out at temperature of from about 0° C. to about 100°C., preferably at 0° C. to 60° C.

Dependent upon the acidic substance used and the reaction conditions,the ester moiety of compound IX may be hydrolyzed along with the ringclosure.

When a piperazine is used in the above reaction, one nitrogen atom ofthe piperazine compound may optionally be protected with a suitableprotective group for example, an acyl group, by techniques per se known,if desired, and the final product obtained thereafter may have theprotective group, or alternatively the protective group may be removedso as to form a final product which does not contain the protectivegroup. The removal of the protective group may also be carried out byprocedures per se known.

In addition, an N-unsubstituted product may be processed by methods perse known so as to introduce a substituent onto the nitrogen atom to givean N-substituted piperazine compound.

Other methods per se known may be used to carry out the N-alkylation,which includes reaction with a halogenated alkyl moiety, a reaction withan ester of alkylsulfuric acid such as dimethylsulfuric acid or asulfonic acid, or a reductive alkylating reaction with an aldehyde. Thereaction conditions for the respective reactions vary in accordance withthe kinds of the reactants and the alkylating agents used, and reactiontemperature, reaction time and the solvent selected.

When the moiety (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl is to beintroduced onto the nitrogen atom, the following method, is suitable:##STR8## wherein A, R¹ and R² are as above defined and X¹ is halo.

Thus, the compounds of the formulae X and XI are reacted in the absenceor presence of an inert solvent in the presence of a base (such assodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, triethylamine, etc.) usually at a temperature of from about-20° C. to about +80° C. (most preferably at -5° C. to ambienttemperature) to produce compounds of the formula Ib.

Preferred solvents used are aprotic ones such as, for example,N,N-dimethylformamide, dimethyl sulfoxide, and ethers including diglyme.

The amount of compound XI to one mole of compound X is preferablyequimolar to an excess. The reaction time may vary depending upon thetypes and amounts of starting materials, solvents and bases as well asreaction temperature but, usually, it may be from about 2 to 20 hours.

When the compounds of the present invention are produced in ester form,these may optionally be hydrolyzed, if desired, to convert them into thecorresponding free carboxylic acids (that is, R² in formula I ishydrogen). The hydrolysis reaction is carried out with a large excessamount of an acid (for example, sulfuric acid, fuming sulfuric acid,hydrochloric acid, hydrobromic acid, hydrobromic acid/acetic acid,chlorosulfonic acid, polyphosphoric acid), preferably using the acid inan amount of from 10 to 20 times by weight as a solvent, at from aboutroom temperature to about 110° C. The esters may also be hydrolyzed in20 to 30 times by weight (preferably 5 to 10 times by weight) of a 1% to5% potassium hydroxide or sodium hydroxide-containing aqueous alcohol(e.g., methanol, ethanol, propanol, butanol, preferably tert.butanol)solvent, at from about room temperature to about 60° C. with stirring.

The esters of the present invention, that is, those wherein R² is alkylmay be transesterified, that is, one ester may be converted to adifferent ester, for example, by heating the ester in 10 to 100 times ofan alcohol which corresponds to the intended ester to be formed by thetransesterification in the presence of a catalytic amount ofconcentrated sulfuric acid, while stirring at a temperature of fromabout 60° C. to about 150° C., preferably at about 100° C. to about 110°C.

When the compounds obtained are in the form of the acid that is R² informula I is hydrogen, such compounds may if desired be esterified. Theesterification reaction can be carried out in accordance with well knownesterification procedures, for example, by the use of thionyl chloridein an alcohol, an alcohol and a condensing agent (e.g.,dicyclocarbodiimide), or an alkyl halide and an alcoholate. In addition,the carboxylic acids may be converted into pharmaceutically acceptablesalts such as for example, the sodium and potassium salts by techniquesknown per se and such salts may also be converted to the correspondingfree acids.

Starting compounds II and VIII may be prepared by those skilled in theart using known methods. Preferred prcoesses are described in JapaneseApplication JP-A-59-227887 and JP-A-59-210093 which are specificallyincorporated herein by reference.

Starting compound VI is new and may be prepared in accordance withMethods-A and B described above. Example A below more particularlyillustrates the preparation of a representative compound of formula VI.

The final products of formula I thus may be isolated and purified byprocedures per se known, for example, by concentration, liquidconversion, conversion dissolution, solvent extraction, crystallization,recrystallization, fractional distillation, chromatography and the like.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they are given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The compounds of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by eye lotion, ointment orsuppository. Administration may also be by injection, infusion orinhalation; topical by lotion or ointment; and rectal by suppositories.Oral administration is preferred.

As to carriers, one or more liquid, solid or semisolid diluent, fillerand other auxillary agents for pharmaceutical preparations may be used.It is desired that the pharmaceutical compositions are administered inunit dosage form.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, capsules, granules and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as, for example, starch or mannitol. Flavoring,preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder as caboxymethyl cellulose, analginage, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds and pharmaceutically accetable acid addition salts of thepresent invention can also be combined with free flowing inert carriersand compressed into tablets directly without going through thegranulating or slugging steps. A clear or opaque protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a nontoxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a nontoxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxyethylene sorbitol esters, preservatives, flavor additives such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations or oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting, water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample flavored aqueous solution, while elixirs are prepared throughmyristyl palmitate or mixtures thereof.

In determining the dosage for treating bacterial infections a number offactors such as the age of the patient, body weight, severity ofcondition, administration route, and the like must be considered.Generally, from about 50 mg to 1 g per day of a compound of the presentinvention should be administered to a human adult preferably from 100 mgto 300 mg per day orally. In some cases, a lower dose is sufficient and,in some other cases, a higher dose or more doses may be necessary. Theadministration may be one to several times a day or with an intermissionof one to several days.

It is preferred that the administration be divided so thatadministration takes place 2 or 3 times per day.

The following nonlimitative examples more particularly illustrate thepresent invention.

EXAMPLE A (1) Ethyl1-methyl-7-methylthio-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylate

5.58 g of potassium carbonate, 18.95 g of ethylidene bromide and 0.34 gof potassium iodide were added to 160 ml of dry N,N-dimethylformamide(DMF) and heated at 115° C. (bath temperature) for 10 minutes. Asolution of 6.00 g of ethyl5-hydroxy-2-methylthio-7-thioxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylateas dissolved in 400 ml of dry DMF was dropwise added thereto over aperiod of 1 hour. The whole was continued to be stirred for further 7hours at the same temperature. The insoluble substances were taken outby filtration and the solvent was taken out by distillation underreduced pressure. The residue was partitioned in chloroform/water,extracted two times with chloroform and washed with an aqueous saturatedsalt solution. The extract was dried with magnesium sulfate and thesovlent was removed by distillation. The residue was recrystallized fromethanol to obtain 4.33 g of the intended compound. m.p. 206° to 207° C.

Elementary Analysis (C₁₃ H₁₃ N₂ O₃ S₂): Calcualted Value (%) C: 48.28,H: 4.05, N: 12.99. Measured Value (%) C: 48.11, H: 3.98, N: 12.93.

(2)1-Methyl-7-methylthio-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicacid

4.10 g of the compound obtained in the above-mentioned step (1) wasdissolved in 50 ml of fuming sulfuric acid and stirred at 60° C. (bathtemperature) for 60 minutes. The reaction solution was poured onto iceand the precipitate formed was collected by centrifugation. This waswashed with water, methanol and ether each three times and dried underreduced pressure to obtain 3.40 g of the intended ocmpound. m.p. 225° to227° C. (decomposition).

Elementary Analysis (C₁₁ H₉ N₃ O₃ S₂): Calculated Value (%) C: 44,74, H:3.07, N: 14.23. Measured Value (%) C: 44.74, H: 2.93, N: 14.12.

(3)1-Methyl-7-methylsulfinyl-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicacid

1.00 g of the compound obtained in the above-mentioned step (2) wasdissolved in 250 ml of chloroform, and 0.77 g of m-chloro-perbenzoicacid (m-CPBA) was gradually added thereto. After stirred for 1 hour, thesolvent was removed by distillation under reduced pressure. The residuewas washed with ethanol and ether and dried under reduced pressure toobtain 0.98 g fo the intended compound.

m.p. 208° to 210° C. (decomposition).

Elementary Analysis (C₁₁ H₉ N₃ O₄ S₂) Calculated Value (%) C: 42.44, H:2.91, N: 13.50. Measured Value (%) C: 41.83, H: 3.03, N: 13.30.

In the same manner, the following compounds were obtained.

7-Methylsulfinyl-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicacid

m.p. 300° C. or higher.

Elementary Analysis (C₁₀ H₇ N₃ O₄ S₂) Calcualted Value (%) C: 40.40, H:2.37, N: 14.13. Measured Value (%) C: 40.06, H: 2.17, N: 14.09.

I R ν_(max) cm⁻¹ : 3000, 1705, 1600, 1580, 1430, 1380, 1340, 1305, 1060,815

EXAMPLE 1 Ethyl7-(4-Acetyl-1-piperadinyl)-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

A solution of 3.0 g of ethyl7-(4-acetyl-1-piperazinyl)-6-fluoro-4-hydroxy-2-mercapto-1,8-naphthyridine-3-carboxylateas dissolved in 150 ml of chloroform and 50 ml of DMF was dropwise addedto a solution obtained by heating and stirring a mixture comprising 4.08g of methylene chloride, 2.54 g of potassium carbonate and 90 ml of DMFat 60° to 65° C., over a period of 2 hours. The whole was stirred forfurther 30 minutes at the same temperature and then water was addedthereto. This was made weakly acidic with acetic acid and extracted withchloroform. The chloroform layer was separated, washed with water, driedand concentrated. Ethanol was added to the resulting residue, and thecrystal formed was taken out by filtration and washed with a smallamount of ethanol to obtain 2.87 g of a pale yellow crystal. m.p. 244°to 246° C. (decomposition).

EXAMPLE 2 6-Fluoro-7-(1-piperazinyl)-4-oxo-4H[1,3]-thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylic AcidHydrochloride

3.6 g of the compound obtained in Example 1 was suspended in 36 ml of a5% aqueous hydrochloride acid solution and heated and stirred at 100° C.for 4.5 hours. After cooled, the crystal precipitated was taken out byfiltration and washed with ethanol and ether in order. The crude crystalthus obtained was recrystallized from ethanol/water (1/1). Thus 2.1 g ofa white powdery crystal was obtained. m.p. 235° C. (decomposition).

Elementary Analysis (C₁₄ H₁₃ FN₄ O₃ S.HCl): Calculated Value (%) C:45.11, H: 3.79, N: 15.03. Measured Value (%) C: 45.14, H: 3.84, N:14.87.

EXAMPLE 36-Fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]-thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Hydrochloride

1.1 g of the compound obtained in Example 2 was suspended in 5 ml fowater and neutralized with 2.35 ml of 5% sodium hydroxide. The crystalprecipitated was taken out by filtration. This was washed with water,ethanol and ether in order. The crystal was dissolved in 3.6 ml offormic acid, and 1.2 ml of a 37% aqueous formalin solution was addedthereto and heated and stirred for 1.5 hours at 110° to 120° C. Aftercooled, this was diluted with ethanol and the crystal precipitated wastaken out by filtration. The crystal was suspended in a small amount ofwater and then dissolved with a 5% aqueous sodium hydroxide solution.The resulting solution was made acidic with a 5% aqueous hydrochloricacid solution and then diluted with ethanol. The crystal precipitatedwas taken out by filtration and recrystallized from a mixed solvent ofethanol and water to obtain 0.84 g of a white powdery crystal. m.p. 240°C. (decomposition).

Elementary Analysis (C₁₅ H₁₅ FN₄ O₃ S.HCl): Calculated Value (%) C:46.57, H: 4.17, N: 14.48. Measured Value (%) C: 46.49, H: 4.14, N:14.24.

EXAMPLE 4 (1) Diethyl3-(5-chloro-6-morpholinylpyridin-2-yl)-[1,3]thiazetidin-2-ylidene-malonate

While 4.10 g of methylene iodide, 2.54 g of potassium carbonate and 80ml of dry DMF were heated and stirred at 50° to 60° C., a solution of3.18 g of diethyl5-chloro-6-morpholino-2-pyridinylaminomercaptomethylene-malonate asdissolved in 160 ml of dry MDF was dropwise added thereto over a periodof 6 hours. After the addition, the reaction mixture was concentratedunder readuced pressure at 50° to 60° C., and the residue was dissolvedin ethyl acetate, washed with water, dried and concentrated. N-hexanewas added to the residue, and the crystal precipitated wasrecrystallized from n-hexane/ethyl acetate to obtain 2.01 g of a whitecrystal. m.p. 142° to 144° C.

(2)6-Chloro-7-morpholino-4-oxo-4H-[1,3]-thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicacid

While 40 g of fuming sulfuric acid was stirred under ice-cooling, 2.01 gof the compound obtained in the above-mentioned step (1) was graduallyadded thereto and stirred at room temperature for 12 hours. The reactionsolution was added to water, and the colloidal crystal precipitate wastaken out by centrifugation. The crystal was washed with water and driedto obtain 1.10 g of a pale yellow crystal. m.p. 254° C. (decomposition).

Elementary Analysis (C₁₄ H₁₂ ClN₃ O₄ S.H₂ O) Calculated Value (%) C:45.23, H: 3.79, N: 11.30. Measured Value (%) C: 45.51, H: 3.30, N:11.29.

EXAMPLE 5 Ethyl6-Chloro-1-methyl-7-morpholino-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

A solution of 6.10 g of ethyl6-chloro-4-hydroxy-2-mercapto-7-morpholino-1,8-naphthyridine-3-carboxylate,6.20 g of ethylidine bromide, 4.56 g of potassium carbonate and 66 mg ofpotassium iodide as dissolved in 660 ml of dry DMF was blended andheated with an oil bath of 100° to 110° C. for 5.5 hours with stirring.After the reaction, the reaction mixture was concentrated at 70° C.under reduced pressure. Ice-water was added to the residue, which wasthen extracted with chloroform. The chloroform layer was washed withwater, dried and concentrated, and the residue thus obtained wascrystallized with ethyl acetate. The crystal was taken out by filtrationand recrystallized from ethyl acetate, to obtain 3.79 g of a pale yellowcrystal. m.p. 192° to 193° C.

Elementary Analysis (C₁₇ H₁₈ ClN₃ O₄ S): Calculated Value (%) C: 51.58,H: 4.58, N: 10.62. Measured Value (%) C: 51.45, H: 4.63, N: 10.62.

EXAMPLE 66-Chloro-1-methyl-7-morpholino-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

While 76 g of fuming sulfuric acid was stirred under ice-cooling, 3.79 gof the compound obtained in Example 5 was gradually added thereto andstirred at room temperautre. After reacted for 12 hours, the reactionsolution was added to ice, and the crystal precipitated was taken out bycentrifugation. This was washed with water and dried to obtain 3.62 g ofa crude crystal. This was recrystallized from DMF to obtain 2.44 g of apale yellow crystal. m.p. 242° C. (decomposition).

Elementary Analysis (C₁₅ H₁₄ ClN₃ O₄ S): Calculated Value (%) C: 48.98,H: 3.84, N: 11.42. Measured Value (%) C: 48.78, H: 3.82, N: 11.16.

EXAMPLE 71-Methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicAcid

0.300 g of the compound obtained in the step (3) of Referential Examplewas suspended in 10 ml of dry DMF. A solution of 0.212 g ofN-methylpiperazine as dissolved in 5 ml of dry DMF was dropwise addedthereto at room temperature. After the addition, the solvent was removedby distillation under reduced pressure, and the residue was dissolved inchloroform. The insoluble substances were taken out by filtration andthe solvent was removed by distillation under reduced pressure. Theresidue was recrystallized from ethanol to obtain 168 mg of the intendedcompound. m.p. 236° to 238° C. (decomposition).

Elementary Analysis (C₁₅ H₁₇ N₅ O₃ S): Calculated Value (%) C: 51.86, H:4.93, N: 20.16. Measured Value (%) C: 51.47, H: 4.72, N: 19.88.

EXAMPLE [ &(4-Acetyl-1-piperazinyl)-1-methyl-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicAcid

0.466 g of the compound obtained in the step (3) of Referential Examplewas suspended in 15 ml of dry DMF. A solution of 0.423 g ofN-acetylpiperazine dissolved in 10 ml of dry DMF was dropwise addedthereto at room temperature and stirred for 30 minutes. After thereaction, the solvent was removed by distillation under reducedpressure, and the crystal fromed was washed with ethanol and dried underreduced pressure to obtain 0.39 g of the intended compound. m.p. 271° to272° C. (decomposition).

Elementary Analysis (C₁₆ H₁₇ N₅ O₄ S): Calculated Value (%) C: 51.19, H:4,56, N: 18.66. Measured Value (%) C: 51.02, H: 4.43, N: 18.46.

EXAMPLE 9 1-Methyl-7-(1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylic Acid

257.5 mf of the compound obtained in Example 8 was suspended in 30 ml of5% hydrochloric acid and refluxed for 3.5 hours. The reaction mixturewas left as such overnight. The crystal precipitated was taken out byfiltration, washed with ethanol and dried under reduced pressure toobtain 57.7 mg of the intended compound. m.p. 300° C. or higher.

Elementary Analysis (C₁₄ H₁₅ N₅ O₃ S.HCl): Calculated Value (%): C:45.47, H: 4.36, N: 18.94. Measured Value (%): C: 45.22, H: 4.44, N:18.80.

I R ν_(max) cm⁻¹ : 3420, 2810, 2405, 1705, 1620, 1455, 1430, 1355, 1325,1025, 810,

In the same manner as Examples 1 to 9, the following compounds wereobtained.

EXAMPLE 10 Ethyl7-(4-Acetyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

m.p. 203° to 205° C.

Elementary Analysis (C₁₉ H₂₁ FN₄ O₄ S): Calculated Value (%) C: 54/28,H: 5.03, N: 13.33. Measured Value (%): C: 54.10, H: 5.04, N: 13.17.

EXAMPLE 11 Ethyl7-(4-Acetyl-1-piperazinyl)-1-ethyl-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

N M R δ (CDCl₃): 1.12(3H, t), 1.37(3H, t), 2.12(3H, s), 3,40˜4.00(8H,m), 4.30(2H, q), 5.50˜6.00(2H, m), 7.90(1H, d)

EXAMPLE 126-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Hydrochloride

m.p. 280° C. (decomposition).

Elementary Analysis (C₁₅ H₁₅ FN₄ O₃ S.HCl): Calculated Value (%) C:46.57, H: 4.17, N: 14.48. Measured Value (%) C: 46.68, H: 4.10, N:14.28.

EXAMPLE 131-Ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 207° to 209° C.

Elementary Anaylsis (C₁₆ H₁₇ FN₄ O₃ S.4H₂ O): Calculated Value (%) C:44.03, H: 5.77, N: 12.84. Measured Value (%) C: 43.75, H: 5.63, N:12.86.

EXAMPLE 146-Fluoro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 250° to 252° C. (decomposition).

Elementary Analysis (C₁₆ H₁₇ FN₄ O₃ S): Calculated Value (%) C: 52.74,H: 4.70, N: 15.38. Measured Value (%) C: 52.81, H: 4.72, N: 14.91.

EXAMPLE 151-Ethyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 237° C.

Elementary Analysis (C₁₇ H₁₉ FN₄ O₃ S.1/2H₂ O): Calculated Value (%) C:52.70, H: 5.20, N: 14.46. Measured Value (%) C: 52.78, H: 4,76, N:14.60.

EXAMPLE 16

Ethyl7-(4-Ethoxycarbonyl-1-piperazinyl)-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

m.p. 205° to 229° C. (decomposition).

Elementary Analysis (C₁₅ H₂₁ FN₄ O₅ S): Calculated Value (%) C: 52.29,H: 4.85, N: 12.84. Measured Value (%) C: 51.94, H: 4.92, N: 12.68.

EXAMPLE 17 Ethyl6-Fluoro-1-methyl-7-morpholino-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

m.p. 198° to 202° C. (decomposition).

Elementary Analysis (C₁₇ H₁₈ FN₃ O₄ S): Calculated Value (%) C: 53.82,H: 4.78, N: 11.08. Measured Value (%) C: 53.64, H: 4.69, N: 10.92.

EXAMPLE 186-Fluoro-1-methyl-7-morpholino-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 249° C. (decomposition).

Elementary Analysis (C₁₅ H₁₄ FN₃ O₄ S): Calculated Value (%) C: 51.28,H: 4.02, N: 11.96. Measured Value (%) C: 51.30, H: 4.02, N: 11.68.

EXAMPLE 196-Fluoro-7-morpholino-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 280° to 283° C. (decomposition).

EXAMPLE 206-Chloro-4-oxo-7-(1-piperazinyl)-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Hydrochloride

m.p. 250° C. (decomposition).

Elementary Analysis (C₁₄ H₁₃ ClN₄ O₃ S.HCl) Calculated Value (%) C:43.20, H: 3.63, N: 14.39. Measured Value (%) C: 43.12, H: 3.39, N:14.23.

EXAMPLE 216-Chloro-1-methyl-4-oxo-7-(1-piperazinyl)-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Hydrochloride

m.p. 280° C. (decomposition).

Elementary Analysis (C₁₅ H₁₅ ClN₄ O₃ S.HCl): Calculated Value (%) C:44.67, H: 4.00, N: 13.89. Measured Value (%) C: 44.69, H: 3,82, N:13.72.

EXAMPLE 22 4-Chloro-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylic Acid

m.p. 240° C. (decomposition).

Elementary Analysis (C₁₅ H₁₅ ClN₄ O₃ S.H₂ O): Calculated Value (%) C:46.82, H: 4.45, N: 14.56. Measrued Value (%) C: 46.80, H: 4.34, N:14.45.

EXAMPLE 236-Chloro-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Ethanesulfonate

m.p. 260° to 263° C.

Elementary Analysis (C₁₅ H₁₅ ClN₄ O₃ S.C₂ H₆ O₃ S.2H₂ O): CalculatedValue (%) C: 39.80, H: 4.91, N: 10.92. Measured Value (%) C: 40.06, H:4.76, N: 10.80.

EXAMPLE 246-Chloro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid

m.p. 252° to 254° C. (decomposition).

Elementary Analysis (c₁₆ H₁₇ ClN₄ O₃ S): Calculated Value (%) C: 50.46,H: 4.50, N: 14.71. Measured Value (%) C: 50.36, H: 4.50, N: 14.58.

EXAMPLE 256-Chloro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylicAcid Ethanesulfonate

m.p. 262° to 264° C.

Elementary Analysis (C₁₆ H₁₇ ClN₄ O₃ S.C₂ H₆ O₃ S.3/2 H₂ O): CalculatedValue (%) C: 41.74, H: 5.06, N: 10.82. Measured Value (%) C: 41.80, H:5.18, N: 10.71.

EXAMPLE 267-(4-Methyl-1-piperazinyl)-4-oxo-4H[1,3]thiazeto[3',2'-1,2]pyrido[2,3-d]pyrimidine-3-carboxylicAcid

m.p. 300° C. or higher.

Elementary Analysis (C₁₄ H₁₅ N₅ O₃ S): Calculated Value (%) C: 50.44, H:4.54, N: 20.52. Measured Value (%) C: 49.90, H: 4.72, N: 20.52.

I R ν_(max) cm⁻¹ : 3400, 1695, 1620, 1465, 970, 805,

EXAMPLE 27 Ethyl7-(4-Acetyl-1-piperazinyl)-6-chloro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthyridine-3-carboxylate

N M R δ (CDCl₃): 1.33(3H, t), 2.11(3H, s) 3.30˜3.90(8H, m), 4.29(2H, q),5.38(2H, s), 8.32(1H, s)

EXAMPLE 28 Ethyl7-(4-Acetyl-1-piperazinyl)-6-chloro-1-methyl-4-oxo-4H[1,3]thiazeto[3,2-a]1,8-naphthyridine-3-carboxylate

N M R δ (CDCl₃): 1.35(3H, t), 2.12(3H, s) 2.13(3H, d), 3.20˜3.90(8H, m),4.30(2H, q) 5.94(1H, q), 8.32(1H, s)

EXAMPLE 29

Ethyl7-(4-acetyl-1-piperazinyl)-6-fluoro-1-phenyl-4-oxo-4H[1,3]thiazeto[3,2-2]-1,8-naphthylidine-3-carboxylate.

Mass analysis (C₂₄ H₂₃ FN₄ O₄ S), M⁺ : 482.

EXAMPLE 30

Ethyl7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(4-fluorophenyl)-4-oxo-4H[1,3]thiazeto[3,2-a]1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₄ H₂₂ F₂ N₄ O₄ S), M⁺ : 500.

EXAMPLE 31

Ethyl7-(4-acetyl-1-piperazinyl)-1-(3,4-difluorophenyl)-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₄ H₂₁ F₃ N₄ O₄ S), M⁺ : 518.

EXAMPLE 32

Ethyl7-(4-acetyl-1-piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₄ H₂₁ F₃ N₄ O₄ S), M⁺ : 518.

EXAMPLE 33

Ethyl7-(4-acetyl-1-piperazinyl)-1-(3,5-difluorophenyl)-6-fluoro-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₄ H₂₁ F₃ N₄ O₄ S), M⁺ : 518.

EXAMPLE 34

6-Fluoro-1-phenyl-7-piperazinyl-4-oxo-4H[1,3]thiazeto[3,2-a]-1,8-naphthylidine-3-carboxylicacid hydrochloride. M.p. 250° C. (decompn.). Mass analysis (C₂₀ H₁₇ FN₄O₃ S.HCl), M⁺ : 448.

Elementary analysis for C₂₀ H₁₇ FN₄ O₃ S.HCl.H₂ O: Calcd: C 51.45, H4.31, N 12.00. Found: C 51.43, H 4.10, N 12.19.

EXAMPLE 35

6-fluoro-1-(4-fluorophenyl)-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. M.p. 260° C. (decompn.). Mass analysis (C₂₀ H₁₆ F₂ N₄ O₃ S), M⁺ :430.

Elementary analysis for C₂₀ H₁₆ F₂ N₄ O₃ S.2H₂ O Calcd (%): C 51.50, H4.32, N 12.01. Found (%): C 49.91, H 4.19, N 12.63.

EXAMPLE 36

1-(2,4-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. M.p. 230° C. (decompn). Mass analysis (C₂₀ H₁₅ F₃ N₄ O₃ S), M⁺ :448.

Elementary analysis for C₂₀ H₁₅ F₃ N₄ O₃ S.H₂ O Calcd (%) C 51.50, H3.67, N 12.01; Found (%) C 51.31, H 3.67, N 11.54

EXAMPLE 37

1-(3,4-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₀ H₁₅ F₃ N₄ O₃ S), M⁺ : 448.

EXAMPLE 38

1-(3,5-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₀ H₁₅ F₃ N₄ O₃ S), M⁺ : 448.

EXAMPLE 39

6-fluoro-7-(4-methyl-1-piperazinyl)-1-phenyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. M.p. 270° C. (decompn.). Mass analysis (C₂₁ H₁₉ FN₄ O₃ S), M⁺ :426.

EXAMPLE 40

6-fluoro-1-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. M.p. 270° C. (decompn.). Mass analysis (C₂₁ H₁₈ F₂ N₄ O₃ S), M⁺ :444.

Elementary analysis for C₂₁ H₁₈ F₂ N₄ O₃ S.H₂ O Calcd (%): C 54.54, H4.36, N 12.11. Found (%): C 54.88, H 4.51, N 11.37.

EXAMPLE 41

1-(3,4-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₁ H₁₉ F₃ N₄ O₃ S), M⁺ : 502.

EXAMPLE 42

1-(2,4-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₁ H₁₉ F₃ N₄ O₃ S), M⁺ : 502.

EXAMPLE 43

1-(3,4-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₁ H₁₉ F₃ N₄ O₃ S), M⁺ : 502.

EXAMPLE 44

Ethyl6-fluoro-7-(4-methyl-1-piperazinyl)-1-phenyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxyalte.

A mixture of 200 mg of the compound obtained in Example 39, 64 mg ofpotassium carbonate, 74 mg of ethyl iodide and 6 ml ofN,N-dimethylformamide were stirred at room temperature for 16 hours. 60ml of water was added to the reaction mixture and then extracted withchloroform. The chloroform layer was washed with water, dried and thenconcentrated and the resultant residue was purified on silica gelchromatography to obtain 120 mg of crystals. M.p. 197°-198° C. Massanalysis (C₂₃ H₂₃ FN₄ O₃ S), M⁺ : 454.

Elementary analysis for C₂₃ H₂₃ FN₄ O₃ S.1/2H₂ O: Calcd (%): C 59.60, H5.21, N 12.09; Found (%) C 59.69, H 5.15, N 11.99.

The following compounds were obtained in the same manner as in Example44.

EXAMPLE 45

Ethyl6-fluoro-1-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxyalte.Mass analysis (C₂₃ H₂₂ F₂ N₄ O₃ S), M⁺ : 472.

EXAMPLE 46

Ethyl1-(3,4-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₃ H₂₁ F₃ N₄ O₃ S), M⁺ : 490.

EXAMPLE 47

Ethyl1-(2,4-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₃ H₂₁ F₃ N₄ O₃ S), M⁺ : 490.

EXAMPLE 48

Ethyl1-(3,5-difluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₃ H₂₁ F₃ N₄ O₃ S), M⁺ : 490.

EXAMPLE 49

1-(2,4-difluorophenyl)-6-fluoro-7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid.

449 mg of the compound obtained in Example 36, 120 mg of potassiumhydrogen carbonate were suspended in 5 ml of N,N-dimethylformamide, towhich 232 mg of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was droppedunder ice cooling and stirred for 3 hours. After the reaction was over,the solvent was distilled off at 60° C. under a reduced pressure. Icedwater was added to the resultant residue and insoluble matters werecollected by filtration, washed with water and then dried in air. Crudecrystals were recrystallized from a chloroform-methanol mixed solutionto obtain an aimed product. M.p. 215° C. (decompn) Mass analysis (C₂₅H₁₉ F₃ N₄ O₃ S), M⁺ : 560.

Elementary analysis for C₂₅ H₁₉ F₃ N₄ O₆ S. Cacld (%): C 53.57, H 3.42,N 10.00; Found (%) C 52.86, H 3.53, N 9.78.

The following compounds were obtained in the same manner as in Example49.

EXAMPLE 50

6-fluoro-7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl)-1-phenyl-4-oxo-4H(1,3)thaizeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₅ H₂₁ FN₄ O₆ S), M⁺ : 524.

EXAMPLE 51

6-fluoro-1-(4-fluorophenyl)-7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₅ H₂₀ F₂ N₄ O₆ S), M⁺ : 542.

EXAMPLE 52

1-(3,4-difluorophenyl)-6-fluoro-7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₅ H₁₉ F₃ N₄ O₆ S), M⁺ : 560.

EXAMPLE 53

1-(3,5-difluorophenyl)-6-fluoro-7-(4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl)-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylicacid. Mass analysis (C₂₅ H₁₉ F₃ N₄ O₃ S), M⁺ : 560.

EXAMPLE 54

Ethyl6-fluoro-1-(4-fluorophenyl)-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.

430 mg of the compound obtained in Example 35 was dissolved in 15 ml of98% formic acid, to which 5 ml of anhydrous acidic acid was droppedunder ice cooling and stirring. After stirring the reaction mixture atroom temperature for 4 hours, it was poured into iced water anddeposited crystals were collected by filtration, washed with water andethanol and then dried. Then, a mixture of the resultant crystals, 138mg of potassium carbonate, 156 mg of methyl iodide and 10 ml ofN,N-dimethylformamide was stirred at room temperature over one night.100 ml of water was added to the reaction solution and extracted withchloroform. The chloroform layer was washed with water, dried and thenconcentrated. Successively, 12 ml of ethanol and 0.24 ml of concentratedsulfuric acid were added to the resultant residue and then refluxedunder heating at 80°-90° C. for 4.5 hours. After condensating thereaction solution under a reduced pressure, 10 ml of water was added,neutralized with sodium hydrogen carbonate and then extracted withchloroform. The chloroform layer was washed with water, dried and thenconcentrated under a reduced pressure. The residue was purified onsilica gel chromatography to obtain the abovecaptioned compound. Massanalysis (C₂₂ H₂₀ F₂ N₄ O₃ S), M⁺ : 458.

The following compounds were obtained in the same manner as in Example54.

EXAMPLE 55

Ethyl6-fluoro-1-phenyl-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₂ H₂₁ FN₄ O₃ S), M⁺ : 440.

EXAMPLE 56

Ethyl1-(3,4-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₂ H₁₉ F₃ N₄ O₃ S), M⁺ : 476.

EXAMPLE 57

Ethyl1-(2,4-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₂ H₁₉ F₃ N₄ O₃ S), M⁺ : 476.

EXAMPLE 58

Ethyl1-(3,5-difluorophenyl)-6-fluoro-7-piperazinyl-4-oxo-4H(1,3)thiazeto(3,2-a)-1,8-naphthylidine-3-carboxylate.Mass analysis (C₂₂ H₁₉ F₃ N₄ O₃ S), M⁺ : 476.

PHARMACEULOGICAL DATA

Compounds representative of the present invention were tested in orderto demonstrate the antibacterial activity of the compounds of thepresent invention.

1. Measurement of Minimal Growth Inhibitory Concentration (MIC) TestMethod

MIC was measured by agar plate dilution assay method in accordance withthe standard by Japan Chemical Therapeutics Association (refer toJournal of Japan Chemical Therapeutics Association, 29 (1), 76 to 79(1981).

Briefly, a bacteria suspension as incubated in a bouillon medium formeasurement of sensitivity, at 37° C. for 18 hours was diluted to 10⁶CFU/ml with the same medium. This was inoculated on an agar medium formeasurement of sensitivity, which contained a compound to be tested,with a microplanter and incubated at 37° C. for 18 hours and then theMIC was measured. Enoxacin was used as a control. The results obtainedare set forth in Table 1 below. As is clear therefrom, the compounds ofthe present invention had an extremely strong bactericidal activityagainst Pseudomonas aeruginosa and other gram-positive bacteria andgram-negative bacteria.

The compounds of the present invention demonstrate a markedantibacterial activity in particular against P. aeruginosa E-2 whereinthe compounds of the present invention showed a higher level of activitythan shown by enoxacin.

2. Remedial Effect against Mouse Infectious Diseases: Test Method

E. coli KC-14 and P. aeruginosa E-2 each were suspended in 4% mucin, and0.25 ml of each of the resulting suspensions was inoculated into theabdominal cavity of ddy male mice (weight: about 20 g, 4-week age, 10mice for one group). The amount of the bacteria inoculated was 5.1×10⁴CFU/mouse for E. coli KC-14 and 7.5×10⁴ CFU/mouse for P. aeruginosa E-2.Two hours after the inoculation of the bacteria, the compound to betested was orally administered once, and the number of the animalsliving after one week was counted. The results obtained were comparedwith those using the control enoxacin. The results are set forth inTable 1 below.

The compounds of the present invention had a strong remedial effect onmouse infectious diseases, in particular, the activity against P.aeruginosa E-2 was higher than enoxacin which is strongly effectiveagainst that bacteria.

The compounds of the present invention are particularly useful fortreating urinary tract infections and chologenic tract infections.

                  TABLE 1                                                         ______________________________________                                        Compound of Example No.                                                                MIC (μg/ml)                                                                              Remedial Effect                                                 (1)  (2)     (3)      (2)   (3)                                      ______________________________________                                        14         0.1    0.0125  0.2    +++   +++                                    2          0.39   0.05    0.39   +     +                                      3          0.39   0.025   0.39   +++   +++                                    12         0.1    0.0125  0.1    +++   +++                                    20         0.78   0.05    0.78   +     -                                      21         0.39   0.025   0.78   +     +                                      25         0.39   0.025   0.78   +     -                                      18         0.1    0.05    0.78   +     -                                      7          1.56   0.1     1.56   ++    -                                                 0.78   0.2     0.78   ++    ++                                     Enoxacin                                                                      34         0.39   0.1     0.39                                                35         0.39   0.1     0.39                                                ______________________________________                                         (1) means S. aureus; (2) means E. coli; and (3) means P.                      (-) means ineffective; (+) means somewhat poorer than enoxacin;               (++) means comparable to enoxacin; and (+++) means extremely effective.  

What is claimed is:
 1. A compound of the formula ##STR9## or apharmaceutically acceptable salt thereof wherein R¹ is hydrogen, loweralkyl or phenyl unsubstituted or substituted by one or two halomoieties, R² is hydrogen or lower alkyl, A CX wherein X is halo, B is Oor NR³ wherein R³ is hydrogen, lower alkyl, acyl, mono-, di- ortri-haloacyl, lower alkoxycarbonyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl.
 2. A compound according to claim 1 wherein R¹ is hydrogen.
 3. Acompound according to claim 1 wherein R¹ is lower alkyl.
 4. A compoundaccording to claim 1 wherein R² is hydrogen.
 5. A compound according toclaim 1 wherein R² is lower alkyl.
 6. A compound according to claim 1wherein R¹ is phenyl unsubstituted or substituted by one or two fluoromoieties.
 7. A compound according to claim 1 wherein B is O.
 8. Acompound according to claim 1 wherein B is NR³, wherein R³ is hydrogen,lower alkyl, straight or branch chain acyl of 1 to 6 carbon atomsunsubstituted or trifluoro substituted, alkoxycarbonyl of 2 to 5 carbonatoms or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.
 9. A compoundaccording to claim 1 in the form of a pharmaceutically acceptable salt.10. A pharmaceutical composition useful for treating bacterialinfections in humans and animals which comprises an antibacteriallyeffective amount of a compound of the formula ##STR10## or apharmaceutically acceptable salt thereof wherein R¹ is hydrogen, loweralkyl or phenyl unsubstituted or substituted by one or two halomoieties, R² is hydrogen or lower alkyl, A CX wherein X is halo, B is Oor NR³ wherein R³ is hydrogen, lower alkyl, acyl, mono-, di- ortri-haloacyl, lower alkoxycarbonyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, in combination with a pharmaceutically acceptable carrier.
 11. Acomposition according to claim 10 wherein R¹ is hydrogen.
 12. Acomposition according to claim 10 wherein R¹ is lower alkyl.
 13. Acomposition according to claim 10 wherein R² is hydrogen.
 14. Acomposition according to claim 10 wherein R² is lower alkyl.
 15. Acomposition according to claim 10 wherein R¹ is phenyl unsubstituted orsubstituted by one or two fluoro moieties.
 16. A composition accordingto claim 10 wherein B is O.
 17. A composition according to claim 10wherein B is NR³, wherein R³ is hydrogen, lower alkyl, straight orbranch chain acyl of 1 to 6 carbon atoms unsubstituted or trifluorosubstituted, alkoxycarbonyl of 2 to 5 carbon atoms or(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.
 18. A composition accordingto claim 10 wherein the compound is in the form of a pharmaceuticallyacceptable salt.
 19. A method of treating bacterial infections in humansand animals which comprises administering to a human or animal in needthereof an antibacterially effective amount of a compound of the formula##STR11## or a pharmaceutically acceptable salt thereof wherein R₁ ishydrogen, lower alkyl or phenyl unsubstituted or substituted by one ortwo halo moieties, R² is hydrogen or lower alkyl, A CX wherein X ishalo, B is O or NR³ wherein R³ is hydrogen, lower alkyl, acyl, mono-,di- or tri-haloacyl, lower alkoxycarbonyl or(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, in combination with apharmaceutically acceptable carrier.
 20. A method according to claim 19wherein R¹ is hydrogen.
 21. A method according to claim 19 wherein R¹ islower alkyl.
 22. A method according to claim 19 wherein R² is hydrogen.23. A method according to claim 19 wherein R² is lower alkyl.
 24. Amethod according to claim 19 wherein R¹ is aryl unsubstituted orsubstituted by one or two or fluoro moieties.
 25. A method according toclaim 19 wherein B is O.
 26. A method according to claim 19 wherein B isNR³, wherein R³ is hydrogen, lower alkyl, straight or branch chain acylof 1 to 6 carbon atoms unsubstituted or trifluoro substituted,alkoxycarbonyl of 2 to 5 carbon atoms or(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.
 27. A method according toclaim 19 wherein the compound is in the form of a pharmaceuticallyacceptable salt.